TY - JOUR
T1 - Induction of Cytochrome P450 Involved in the Accelerated Blood Clearance Phenomenon Induced by PEGylated liposomes in Vivo
JF - Drug Metabolism and Disposition
JO - Drug Metab Dispos
DO - 10.1124/dmd.118.085340
SP - dmd.118.085340
AU - Wang, Feng L
AU - Wu, Yi F
AU - Zhang, Ji W
AU - Wang, Hui H
AU - Xie, Xiao T
AU - Ye, Xi
AU - Peng, Dai Y
AU - Chen, Wei D
Y1 - 2019/01/01
UR - http://dmd.aspetjournals.org/content/early/2019/01/23/dmd.118.085340.abstract
N2 - Polyethylene glycol (PEG) is recognized as an attractive excipient to modify liposomes due to their extended-circulation properties. Nevertheless, intravenous injection of PEGylated liposomes (PEG-L) usually trigger a rapid systemic clearance of the subsequent dose from blood circulation that is referred to as "accelerated blood clearance (ABC)" phenomenon. Since the induction of cytochrome P450 (CYP) activity may lead to enhanced drug clearance, it therefore motivated us to investigate the possibility of CYPs involvement in the ABC phenomenon. In this study, PEGylated liposomal docetaxel (PEG-DTX-L) was prepared and used to evaluate the magnitude of the ABC phenomenon in rats induced by repeated injection of PEG-modified liposomes. Notably, ABC phenomenon was observed when the time interval between two doses was from 1 to 7 days, and its magnitude reached the maximum level at 3 days before gradually decreasing. Meanwhile, increased activity of CYP3A1, CYP2C6 and CYP1A2 were detected when PEG-L were repeatedly injected to male rats with a 3 days interval. Consistently, the expression levels of hepatic CYP3A1, CYP2C6 and CYP1A2 were also significantly increased in the repeated injection groups and their levels were highest in the 3-day interval group. CYP selective inhibitors confirmed the inhibition of hepatic CYP3A1 was accompanied by an attenuated magnitude of the ABC phenomenon, which strongly suggests that CYPs may be induced by repeated injection of PEG-L, thus favoring metabolic clearance of the second dose. Collectively, we herein for the first time demonstrate that the contribution of CYPs should not be ignored in the ABC phenomenon.
ER -